Changes Of Vasoconstrictive Response And Barrier Function In Different Basic Diseases After Shock And Selection Of Preventive And Therapeutic Drugs

Both peacetime and wartime,the incidence and mortality of shock are very high.Vascular dysfunction is the main cause of shock-induced organ dysfunction.Vascular dysfunction mainly includes vascular contractive response dysfunction(vascular hypoveactivity)and vascular barrier dysfunction.Vascular hyporeactivity is the weakening or non-responsiveness of blood vessels to vasoactive drugs,which greatly affects the outcome of shock.Vascular barrier dysfunction is due to increased endothelial cell permeability,leakage of macromolecule proteins or lipids into interstitial space,resulting in tissue edema and organ dysfunction.In recent years,the incidence of diabetes,hypertension and hyperlipidemia has been increasing year by year.It is not clear the diversity of vascular contractive response and barrier function with these basic diseases after shock.In this study,hemorrhagic shock model and septic shock model were used for investigating the changes of contractive response and barrier function in different basic diseases after shock and selection of preventive and therapeutic drugs.Methods:Part I Changes of vascular reactivity and selection of vasoactive agents in different basic diseases after hemorrhagic shock1.Changes of vascular reactivity in different basic diseases after hemorrhagic shock: With healthy,diabetic,hypertensive and hyperlipidemia rats were used for replicating two kinds of hemorrhagic shock models,the changes of vasoconstriction reactivity,hemodynamics,hepatorenal blood flow and survival time/survival rate after hemorrhagic shock were observed.2.Selection of antishock drugs in different basic diseases after hemorrhagic shock: With healthy,diabetic,hypertensive and hyperlipidemia rats were used for replicating the model of hemorrhagic shock,the effects of different dosage of common antishock agents(5,10,15,30,50?g/kg/min of norepinephrine [NE],1,3,5,10,15?g/kg/min of dopamine [DA],and 0.04,0.1,0.4,1,4U/kg of arginine vasopressin[AVP])in diseases rats and healthy rats with hemorrhagic shock were observed.The changes of mean arterial pressure(MAP),blood flow of liver and kidney,and survival time/survival rate were observed.3.Effects of antivascular hyporeactivity drugs in different basic diseases after hemorrhagic shock: With healthy,diabetic,hypertensive and hyperlipidemia rats were used for replicating hemorrhagic shock model,the effects of vasoconstriction reactivity,hemodynamics and survival time of AVP and phorbol-12 myrestate-13-acetate(PMA)in diseases rats and healthy rats with hemorrhagic shock were observed.Part II The role of mitochondrial division in vascular leakage after septic shock and the preventive and therapeutic effect of Mdivi-11.The role of mitochondrial division in vascular leakage after septic shock: With healthy SD rats were used for replicating septic shock model at animal level and vascular endothelial cells(VEC)were stimulated by lipopolysaccharide(LPS)at cell level.The changes of mitochondrial morphology,mitochondrial function and vascular leakage of vascular endothelial cells after septic shock were observed.And the role of mitochondrial division in vascular leakage after septic shock were identified.2.The preventive and therapeutic effect of Mdivi-1 in vascular leakage after septic shock: With healthy SD rats were used for replicating septic shock model at animal level and vascular endothelial cells were stimulated by LPS at cell level.The effects of mitochondrial morphology,mitochondrial function and vascular leakage of vascular endothelial cells after septic shock were observed and the preventive and therapeutic effect of mitochondrial division inhibitor-1(Mdivi-1)in vascular leakage after septic shock were clarified.Results:Part I Changes of vascular reactivity and selection of vasoactive agents in different basic diseases after hemorrhagic shock1.Compared with healthy rats,the contractile response of thoracic aorta,superior mesenteric artery and left renal artery to NE was significantly higher before hemorrhagic shock(P<0.01),of which hypertensive rats had the highest vasoconstrictive reactivity;After hemorrhagic shock,the contractile response to NE were decresed significantly both in healthy rats and diseases rats,but the loss rates of contractile response in diseases rats were more than in healthy rats(P<0.01).The blood flow and mitochondrial function of liver and kidney decreased significantly in basic diseases rats after hemorrhagic shock(P<0.01).Compared with healthy rats,the blood flow,mitochondrial function of liver and kidney decreased significantly(P < 0.05 or P < 0.01),and the survival time was shorter(P < 0.01).2.The common antishock drugs including AVP,NE,DA were effective increasing the mean arterial pressure,blood flow of liver and kidney and survival time after hemorrhagic shock both in healthy rats and in diseases rats.There was no dose difference in the therapeutic effects in healthy rats.Low dose of AVP(< 0.4U/kg),NE(< 15ug/kg/min),DA(< 5ug/kg/min)could increase MAP,blood flow of liver and kidney and survival time in diseases rats.The therapeutic effects of high dose of AVP,NE,or DA were worse than low dose.Among the different antishock drugs,effects of AVP were the best.3.AVP and PMA could improve vasoconstriction reactivity(P < 0.05 or P < 0.01)and improve hemodynamics and prolong survival time(P < 0.05 or P < 0.01)after hemorrhagic shock both in healthy rats and in diseases rats.The beneficial effect of AVP was better than PMA.Part II The role of mitochondrial division in vascular leakage after septic shock and the preventive and therapeutic effect of Mdivi-11.After septic shock,mitochondrial division of vascular endothelial cells were increased,mitochondrial functions were decreased,vascular leakage of lung,kidney and intestine were increased.The increase of vascular leakage was positive correlatied with mitochondrial over-division.LPS induced mitochondrial division in vascular endothelial cell,and then resulted in mitochondrial dysfunction and barries destruction.The results indicate that mitochondrial division played an important role in the increase of vascular leakage after septic shock.2.Mitochondrial division of VEC was decreased after Mdivi-1 treatment,mitochondrial functions of liver and kidney were improved and vascular leakage of lung,kidney and intestine were decreased.Conclusion:1.The vascular reactivity after hemorrhagic shock in diseases rats exist diversity.As compared with healthy rats,the loss rate of vascular reactivity after hemorrhagic shock was higher in diseases rats.The blood flow and mitochondria function of liver and kidney were worse,and the survival time was shorter in diseases rats.2.Antishock drugs including AVP,NE,and DA were effective improving blood and survival both in healthy rats and in diseases rats subjected to hemorrhagic shock,their effective dosage range were different.The effective dosage range in diseases rats were narrower.Only lower doses of AVP,NE,and DA increased the MAP,the blood flow of liver and kidney and the animal survival for diseases rats;higher doses of AVP,NE,and DA did not further improve the therapeutic effects.The doses of AVP <0.4U/kg,NE <15ug/kg/min and DA <5ug/kg/min were proper for treatments of diseases rats after hemorrhagic shcok.3.Antivascular hyporeactivity measures AVP and PMA had beneficial effects on healthy rats and diseases rats after hemorrhagic shock.AVP and PMA improved organ blood flow and vra increasing vascular hyporeactivity.The effect of AVP was better than that of PMA.4.Mitochondrial division played an important role in the increase of vascular permeability in septic shock.Mitochondrial division inhibitor-1(Mdivi-1)could prevent the increase of vascular permeability in septic shock.